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Thieno-pyrimidines, useful as potassium channel inhibitors

a potassium channel inhibitor and thienopyrimidine technology, applied in the field of compounds, can solve the problems of side effects precluding its long-term use, ischemic insults,

Inactive Publication Date: 2016-03-22
XENTION LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These compounds effectively terminate and prevent the recurrence of atrial fibrillation and flutter by specifically targeting atrial tissue, reducing the risk of thromboembolic complications and maintaining sinus rhythm without affecting ventricular function.

Problems solved by technology

However, side-effects preclude its long term use (1973).
Pathological thrombosis formation can lead to vascular occlusion, resulting in ischemic insults.

Method used

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  • Thieno-pyrimidines, useful as potassium channel inhibitors
  • Thieno-pyrimidines, useful as potassium channel inhibitors
  • Thieno-pyrimidines, useful as potassium channel inhibitors

Examples

Experimental program
Comparison scheme
Effect test

specific embodiments

[0185]In one embodiment:

[0186]A is S;

[0187]X is N;

[0188]V is CR3III;

[0189]Z is N;

[0190]R1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0191]R2 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, —NR4R5, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —CO2R7, optionally substituted oxazolinyl, —SR14, —S(O)R14 and —S(O)2R14;

[0192]R3I is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —CO2R7, —NR8R9, —C≡C-J, optionally substituted cycloalkyl-J and —(NRaRb)-J;

[0193]R3III is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(O)R7, —NR6S(...

example 58

[1169]4-[4-(Bromomethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidine (13.8 g, 35.5 mmol), 2-(1-methylpyrrolidin-2-yl)ethanamine (5.47 g, 42.6 mmol) and potassium carbonate (7.37 g, 53.3 mmol) were heated in acetonitrile (100 mL) in the microwave at 150° C. for 30 minutes in 8×20 mL microwave vials. The reaction mixtures were combined and diluted with DCM (250 mL). The organic was washed with water (250 mL) and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM to 90:10:1 DCM / MeOH / NH4OH to afford the target compound (4.0 g) and mixed fractions. LCMS [M+H]+=436.0

[1170]Other compounds prepared by Method A as described for example (iii) using the appropriate starting materials are listed in TABLE 1.

Method B

Synthesis of 1-[4-[4-[[methyl-(1-methylpyrrolidin-3-yl)amino]methyl]-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]pyrrolidine-3-carboxamide

Example 120

[1171]i) [1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-...

example 120

[1189]N—[[1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]-N,1-dimethyl-pyrrolidin-3-amine (100 mg, 0.219 mmol) and pyrrolidine-3-carboxamide (300 mg, 2.63 mmol) were stirred in dry acetonitrile (1.5 ml) and heated in a microwave at 140° C. for 0.5 h. The solvent was evaporated and the crude residue purified by flash column chromatography (0 to 5% 7.0M NH3 / MeOH in dichloromethane) to give 1-[4-[4-[[methyl-(1-methylpyrrolidin-3-yl)amino]methyl]-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]pyrrolidine-3-carboxamide as an off white solid (25 mg, 21%). m / z (M+H)+534.3, RT=2.69 min.

[1190]Other compounds prepared by Method B as described for example (iv) using the appropriate starting materials are listed in TABLE 1.

Method C

Synthesis of N,N-dimethyl-5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)cyclohexyl]thieno[2,3-d]pyrimidine-6-carboxamide

Example 135

[1191]i) Methyl 5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine-6-carboxylate

[1...

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Abstract

The present invention provides compounds of formula (I): (Formula (I); wherein A, R1, R2, R3I, V, X, and Z are defined herein, which are potassium channel inhibitors. The invention further provides pharmaceutical compositions comprising the compounds of formula (I) and their use in therapy, in particular in treatment of diseases or conditions that are mediated by Kir3.1 and / or Kir3.4 or any heteromultimers thereof, or that require inhibition of Kir3.1 and / or Kir3.4 or any heteromultimers thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a U.S. national stage application under 35 U.S.C. §371 of International Application No. PCT / GB2012 / 052842, filed Nov. 15, 2012, and published as WO / 2013 / 072694 on May 23, 2013, which claims priority to GB Application No. 1119703.5, filed Nov. 15, 2011, and to GB Application No. 1214250.1, filed Aug. 9, 2012, the contents of each of which are incorporated by reference in their entireties, and to each of which priority is claimed.TECHNICAL FIELD[0002]The present invention relates to compounds of formula (i) which are potassium channel inhibitors. Pharmaceutical compositions comprising the compounds, their use in therapy and methods of treatment employing the compounds are also provided.BACKGROUND ART[0003]Ion channels are proteins that span the lipid bilayer of the cell membrane and provide an aqueous pathway through which specific ions such as Na+, K+, Ca2+ and Cl− can pass (Hille et al., 1999). Potassium channel...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D495/04A61P9/06A61K31/519C07D491/048
CPCC07D495/04A61K31/519C07D491/048C07D519/00A61P3/10A61P5/00A61P9/00A61P9/06A61P9/08A61P9/10A61P15/00A61P25/00A61P25/04A61P25/08A61P25/22A61P25/24A61P35/00
Inventor MADGE, DAVIDCHAN, FIONAJOHN, DEREK EDWARDEDWARDS, SIMON D.BLUNT, RICHARDHARTZOULAKIS, BASILBROWN, LINDSAY
Owner XENTION LTD
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